The development of nucleoside analogues with novel mechanisms of action capable of overcoming HIV resistance is the main focus of this project. Current emphasis include two main classes of structures: 1) 4'-alkyl-2'-deoxynucleosides. These compounds were synthesized with the objective of achieving "delayed chain termination" of viral DNA synthesis catalyzed by HIV reverse transcriptase. The rationale for this approach was based on our findings with locked carbocyclic nucleosides (see project Z01 BC 006174) where we showed that a nucleoside containing a pseudosugar locked in the North conformation could efficiently block DNA synthesis by HIV-1 RT and overcome drug resistance due to excision in resistant variants of HIV-1 RT. In this project, we addressed the question of whether the same objective was achievable with structurally simpler conventional nucleosides bearing a 4'-substituent. In order to investigate the importance of the size of the 4'-alkyl group, the 4'-Methyl and 4'-Ethyl analogues were synthesized. The 4'-Ethyl analogue because of its size behaved as a strict chain terminator, whereas the 4'-Methyl analogue behaved as a delayed chain terminator. Studies with the 4'-Methyl analogue of thymine are in progress to determine its efficacy in avoiding the excision reaction typical of resistant HIV RTs. 2) 2',3'-Dideoxybicyclo3.1.0hexene nucleosides. Having identified the conformationally locked analogues North-MCD4T as a very effective anti-HIV agent, the South equivalent analogues are being pursued. Syntheses of the thymine and adenine analogues have been completed and the guanine and cytosine analogues are at an advanced stage.